1. Field of the Invention
The present invention relates generally to the fields of chemistry and cancer treatment. More specifically, the present invention relates to novel retinoids and their use in chemoprevention and cancer therapy.
2. Description of the Related Art
In chemical descriptions that follow, E may be interchanged synonymously with trans, and Z may be interchanged synonymously with cis.
Retinoid receptors and other this superfamily of nuclear receptors (that include the steroid, thyroid and vitamin D hormone receptors and other "orphan" receptors without known ligands) are new targets for drug development (1). It is thought that retinoic acid (RA) and synthetic retinoids act a s ligand-dependent transcription factors with different members of nuclear retinoid receptors to control gene transcription responsible for cellular proliferation, differentiation, development and cell death (2). Two classes of nuclear retinoid receptors (RARs and RXRs) have been identified so far, and each has several different subtypes (.alpha., .beta., .gamma.). Both (all-E)- and (9Z)-RA bind to RARs and activate transcription mediated by RAR/RXR heterodimers, but (9Z)-RA is the only known natural ligand for the RXRs which mediate transcription by forming homodimers or heterodimers.
Recent advances in chemoprevention have heightened interest in the use of retinoids in several types of solid organ tumors, and major therapeutic successes have been demonstrated with retinoids in certain leukemias (3). (all-E)-RA treatment of patients with acute promyelocytic leukemia (APL) leads to a 90% complete remission rate in these patients by inducing normal maturation and apoptosis of APL myeloblasts to neutrophils, but this differentiation therapy is transient and is commonly followed by relapse within 3-15 months, probably due to the development of resistance to retinoic acid (4). (13Z)-RA effectively controls the excessive myeloproliferation in up to 50% of children with juvenile myelomonocytic leukemia (JMML) (5). However, this treatment is not curative and at best can lead to a period of prolonged stabilization of disease, but ultimately patients need to undergo allogenic bone marrow transplantation (4, 6).
All-trans-retinoic acid (ATRA) is the first example of a FDA-approved agent used for differentiation therapy (rather than standard cytotoxic cancer chemotherapy) of patients with APL. Even though it has been shown to be highly effective in APL treatment, clinical resistance occurs frequently with pharmacological doses of ATRA and APL patients often relapse (Degos et al., 1995, Blood, 85, 2643). In order to provide more effective therapies, new highly active retinoids need to be identified in the expectation that lower doses of these agents would not induce relapse as rapidly as ATRA.
The NB4 cell line, which was isolated from an APL patient undergoing ATRA therapy, offers an excellent in vitro model of APL. The t(15;17) translocation, which is characteristic of APL, is stably carried in NB4 cells, and the PML/RAR-a fusion protein is expressed in this transformed cell line (Lanotte et al, 1991, Blood, 77:1080). ATRA treatment of NB4 cells remove the PML/RAR-a block to differentiation and allow the promyelocytes to mature normally and die. The mechanism by which ATRA removes the differentiation block is not well understood. Recent evidence suggests that ATRA downregulates the expression of PML/RAR-a and restores the normal myleoid differentiation (Raelson et al., 1996 Blood, 88, 2826).
The prior art is deficient in effective therapeutic agents with the beneficial effects of retinoic acid but which have reduced side effects. The present invention fulfills this long-standing need and desire in the art.